Amorphous dispersion of 4-methyl-3-quinolin-3-ylethynyl-benzoic acid n&#39;-(2-chloro-6-methyl-benzoyl) hydrazide

ABSTRACT

An oral solid dosage form comprising a mixture of compound of formula I and a fusible polymeric carrier; and optionally pharmaceutically acceptable excipients, wherein the mixture is an amorphous dispersion.

FIELD OF INVENTION

The present invention relates to an amorphous dispersion of4-Methyl-3-quinolin-3-ylethynyl-benzoic acidN′-(2-chloro-6-methyl-benzoyl)hydrazide and an oral solid dosage formcomprising the amorphous dispersion.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 9,024,021 discloses a compound of Formula I(4-Methyl-3-quinolin-3-ylethynyl-benzoic acidN′-(2-chloro-6-methyl-benzoyl)hydrazide).

Compound of Formula I is a potent inhibitor of Abl tyrosine kinase.Conventional oral solid dosage forms of compound of Formula I failed toprovide adequate bioavailability. There remains a need to provide thecompound of formula I in a bioavailable form. There is a need for anoral solid dosage form of the compound of formula I that has adequatebioavailability and stability.

SUMMARY OF THE INVENTION

The present inventors have discovered novel amorphous dispersion ofcompound of Formula I in a fusible polymeric carrier and oral soliddosage form comprising the amorphous dispersion. The oral solid dosageform of the amorphous dispersion provides enhanced bioavailability aswell as stability.

In a preferred embodiment, the present invention provides an oral soliddosage form comprising a mixture of a compound of formula I

and a fusible polymeric carrier, wherein the mixture is an amorphousdispersion. The oral, solid dosage form optionally comprises ofpharmaceutically acceptable excipients. The amorphous dispersion in theoral solid dosage form of the invention is physically and chemicallystable during melt processing and the oral, solid dosage form remainsstable on storage. Particularly, when the oral solid dosage form isstored at room temperature for 24 months, each of the degradationimpurity such as stage V impurity and N-oxide impurity is less than 0.2%by weight of the compound of formula I and the total impurity, which isa sum of known and unknown impurities, is less than 2% by weight of thecompound of formula I. Further, the compound of formula I remained in anamorphous state during the period of storage.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. X-ray diffraction spectrum exhibits peaks characteristic ofcrystalline form of compound of formula I.

FIG. 2. X-ray diffraction spectrum of a fusible polymeric carrier,namely, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycolcopolymer.

FIG. 3. X-ray diffraction spectrum of a physical mixture of fusiblepolymeric carrier, namely, polyvinyl caprolactam-polyvinylacetate-polyethylene glycol copolymer and compound of formula I. Thegraph exhibits X-ray diffraction peaks characteristic of the crystallineform of compound of formula I.

FIG. 4. X-ray diffraction spectrum of amorphous dispersion of compoundof formula I in a fusible polymeric carrier, namely, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer. The graphdid not exhibit any X-ray diffraction peak characteristic of thecrystalline form of compound of formula I.

FIG. 5. Differential scanning calorimetry analysis (DSC) of compound offormula I in the crystalline form.

FIG. 6. Differential scanning calorimetry analysis (DSC) of theexcipient blend of capsules of Example IV (placebo), in which theamorphous dispersion contains only the fusible polymeric carrier withoutthe inclusion of compound of formula I.

FIG. 7. Differential scanning calorimetry analysis (DSC) of the physicalmixture of the compound of formula I, fusible polymeric carrier andother excipients of Example IV.

FIG. 8. Differential scanning calorimetry analysis (DSC) of the capsulefill of Example IV, at initial time point when the capsules are storedin closed container with desiccant at 40° C. and 75% relative humidity.

FIG. 9. Differential scanning calorimetry analysis (DSC) of the capsulefill of Example IV, on storage in closed container with desiccant at 40°C. and 75% relative humidity for a period of 6 months.

DESCRIPTION OF THE PRESENT INVENTION

The present invention provides an oral, solid dosage form comprising amixture of compound of formula I

and a fusible polymeric carrier; and

optionally pharmaceutically acceptable excipients, wherein the mixtureis an amorphous dispersion.

According to the present invention, the mixture of compound of Formula Iand fusible polymeric carrier is an amorphous dispersion. The amorphousnature of the dispersion of compound of formula I may be determined bytechniques known in the art. In one instance, the amorphous nature isdetermined by recording the X-ray Powder Diffraction (XRD) or byDifferential scanning calorimetry analysis (DSC). The XRD spectrum ofcompound of formula I showing the X-ray diffraction peaks characteristicof the crystalline form is provided in FIG. 1 and the DSC is provided inFIG. 5. The XRD spectrum of fusible polymeric carrier namely, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer is providedin FIG. 2.

The term ‘amorphous dispersion’ as used herein means a solid dispersionof mixture of compound of formula I in a fusible polymeric carrier thatdoes not exhibit X-ray diffraction peaks characteristic of thecrystalline form of compound of formula I or the dispersion that doesnot exhibit the melting peak of the crystalline compound of formula I ina Differential scanning calorimetry analysis (DSC). The XRD spectrum ofamorphous dispersion of compound of formula I in fusible polymericcarrier is provided in FIG. 4 which shows absence of X-ray diffractionpeaks characteristic of crystalline form of compound of formula I. Incontrast, the XRD of the physical mixture of crystalline compound offormula I and fusible polymeric carrier, exhibited X-Ray Diffractionpeaks characteristic of crystalline form of the compound of Formula I,as depicted in FIG. 3. FIG. 4 clearly shows the amorphous state ofcompound of formula I in a fusible polymeric carrier.

The term ‘stable’ or ‘stability’ as used herein means that the dosageform is physically and chemically stable. The ‘chemically stable’ meansthat the oral solid dosage form when stored at room temperature for 24months, each of the degradation impurity such as stage V impurity andN-oxide impurity is less than 0.2% by weight of the compound of formulaI and the total impurity, which is a sum of known and unknownimpurities, is less than 2% by weight of the compound of formula I. Theknown degradation impurities of compound of formula I are named asN-oxide impurity and stage V impurity.

Name of the impurity Chemical Name Chemical Structure N-oxide impurity3-(1-Hydroxy-quinolin- 3-ylethynyl)-4-methyl- benzoic acid N′-(2-chloro-6-methyl- benzoyl)hydrazide

Stage V impurity 4-Methyl-3-quinolin-3- ylethynyl-benzoic acid

‘Physically stable’ means that when the oral solid dosage form of thepresent invention is stored at room temperature, the compound of formulaI remain in an amorphous state.

The fusible polymeric carrier used in the amorphous dispersion of theoral solid dosage form of the present invention may be any fusiblepolymeric carrier that forms an amorphous dispersion with compound offormula I when the mixture of the fusible polymeric carrier and compoundof formula I is processed by melt processing. According to one specificembodiment, the fusible polymeric carrier present in the amorphousdispersion of the present invention, is amphiphilic in nature and issoluble in aqueous medium as well as organic solvents such as alcohols,acetone, dimethylformamide and the like. Examples of such polymersinclude block copolymers of ethylene oxide and propylene oxide,polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer,vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycols havingmolecular weight of 1000 or more which are solid at room temperature, ormixtures thereof. According to an embodiment, the fusible polymer ispolyethylene glycol having average molecular weight more than 1000 suchas 1000, 2000, 1450, 1540, 2000, 3000, 3350, 4000, 4600, 8000 andmixtures thereof and the like. In one preferred embodiment, the fusiblepolymeric carrier is polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer. It is soluble in water,acetone, methanol, ethanol and dimethylformamide; and is available in anaverage molecular weight in the range of 1,000 g/mol to about 5,000,000g/mol. The polymer does not show any chemical degradation when meltprocessed. Preferably, the molecular weight is in the range from about10,000 Wino′ to about 500,000 g/mol. In one preferred embodiment themolecular weight is in the range from about 90,000 g/mol to about140,000 g/mol. In yet another preferred embodiment, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer has amolecular weight in the range of from about 140,000 g/mol to 500,000g/mol. According to one preferred embodiment of the invention, theamorphous dispersion is free of any other excipients. According to otherembodiment, additional excipients may be present in the amorphousdispersion in limited amounts. The fusible polymeric carrier may befirst selected by melt processing a mixture of compound of formula I andthe fusible polymeric carrier and performing a suitable test such asX-Ray Diffraction or Differential Scanning calorimetry to find thatamorphous dispersion is formed. Those polymers when subjected to heatingnear the melting point of the compound of formula I substantiallydegrade or decompose are not within the scope of the term ‘fusiblepolymeric carrier’. Examples of such polymers include, but are notlimited to, cellulose derivatives, such as for example, hydroxypropylcellulose, hydroxypropyl methyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methyl cellulose phthalate,acrylate polymers such as poly (methacrylic acid co-ethyl acrylate 1:1),poly (butylmethylacrylate co-dimethylaminoethyl methacrylate co-methylmethacrylate (1:2:1) and similar such polymers.

In one preferred embodiment, the amorphous dispersion contains compoundof Formula I in the range from 0.1 to 30% by weight of the amorphousdispersion, for example 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or30% by weight of the amorphous dispersion. The fusible polymeric carrieris present in the range from 10 to 99% by weight of the amorphousdispersion, for example 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97,98, or 99% by weight of the amorphous dispersion. In one particularembodiment, the weight ratio of fusible polymeric carrier to compound offormula I is present in the range from 1 to 20, for example 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13 and so on. Preferably, the weight ratio offusible polymeric carrier to compound of formula I is present in therange from 4:1 to 14:1. More preferably, the weight ratio of fusiblepolymeric carrier to compound of formula I is about 7:1.

According to a preferred embodiment, the amorphous dispersion of fusiblepolymeric carrier and compound of formula I

is prepared by a process of melting the mixture of the two componentsi.e. compound of Formula I and fusible polymeric carrier by a suitabletechnique such as hot melt extrusion.

The preferred methods of preparing the amorphous dispersion may be bymelt processing, however it is also possible and within the scope of thepresent invention to prepare the amorphous dispersion by other methodsas described herein. Melt process generally involves mixing the compoundof formula I with a fusible polymeric carrier and heating to form amolten solution. According to another embodiment, the mixture of thefusible polymeric carrier and the compound of formula I may be heated toa temperature near melting point of the fusible polymeric carrier whilemixing or agitating to dissolve the compound of formula I in the moltenfusible polymeric carrier. The hot melt solution is then cooled toobtain the amorphous dispersion. In another embodiment, the mixture ofthe compound of formula I and the fusible polymeric carrier is heated toa temperature near the melting points of the compound of formula I whichhas a melting point of 246±2° C. In another more particularly preferredembodiment, the amorphous dispersion may be obtained by hot meltextrusion. The fusible polymeric carrier is mixed with thetherapeutically effective amount of compound of formula I and subjectedto hot melt extrusion. The hot melt extrusion may be carried out bysubjecting the mixture to gradual increase in temperature, starting from100° C. to 300° C., followed by cooling at ambient temperature.According to the embodiments where the mixture is melted, the moltensolution obtained may be cooled and solidified, and the solid mass iscrushed and pulverized in a suitable mill to obtain the amorphousdispersion in the form of granules or powder.

According to another embodiment, the amorphous dispersion of thecompound of formula I may also be prepared by dissolving the compound offormula I and fusible polymeric carrier in a common solvent andevaporating it until a clear, solvent free film is formed. Other methodof preparation of amorphous dispersion is by dissolving the compound offormula I in a suitable liquid solvent and then incorporating thesolution directly into the melt of a fusible polymeric carrier which isthen evaporated until a clear, solvent free film is formed. The film maybe further pulverized to suitable size by conventional techniques. Theamorphous dispersion obtained by any of the methods described above, isclear and transparent in appearance. The amorphous dispersion of thepresent invention is generally pulverized. The pulverization of theamorphous dispersion may be done by any conventional technique. Thepulverized amorphous dispersion is free flowing and has acceptablecompressibility. The bulk density of the pulverized amorphous dispersionof present invention is less than 0.7 g/ml, preferably 0.4, 0.5, 0.6g/ml. In one specific embodiment, the bulk density is 0.52, 0.53, 0.54,0.55, 0.56 g/ml.

In one embodiment, the amorphous dispersion is obtained in the solidform. The mass is pulverized using known techniques to obtain powder.The particle size of the pulverized amorphous dispersion may be lessthan 1000 microns, preferably, less than 750 microns, most preferably,less than 500 microns. In one specific embodiment, the particle size isin the range of about 75 microns to 425 microns. In one preferredembodiment, the size of the pulverized amorphous dispersion is below 600microns, preferably below 425 microns and more preferably below 180microns. Preferably, the size of the particles is below 425 microns.According to an embodiment, about 100% of the particles of thepulverized amorphous dispersion are of size less than 425 microns.According to another embodiment, about 85% of the particles are of sizeless than 250 microns. According to one another embodiment, about 65% ofthe particles are of size less than 180 microns. According to oneanother embodiment, about 45% of the particles are of size less than 150microns. According to yet another embodiment, about 15% of the particlesare of size less than 75 microns.

In one specific embodiment, the present invention provides an oral,solid dosage form comprising a mixture of compound of formula I

and a fusible polymeric carrier; and

optionally pharmaceutically acceptable excipients, wherein the mixtureis an amorphous dispersion, further wherein the fusible polymericcarrier is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycolgraft co-polymer. In a preferred embodiment, the weight ratio of thefusible polymeric carrier to compound of formula I is about 7:1.Generally, the amorphous dispersion is in the micronized form. Theamorphous dispersion when in the pulverized form, all the particles havesize less than 750 microns, preferably less than 500 microns.

In one another specific embodiment, the present invention provides anoral, solid dosage form comprising a mixture of compound of formula I

and a fusible polymeric carrier; and

optionally pharmaceutically acceptable excipients, wherein the mixtureis an amorphous dispersion, further wherein the fusible polymericcarrier may be polyvinyl caprolactam-polyvinyl acetate-polyethyleneglycol graft co-polymer. In preferred embodiment, the weight ratio ofthe fusible polymeric carrier to compound of formula I is about 7:1.Generally, the amorphous dispersion is in the micronized form. Theamorphous dispersion when in the pulverized form, all the particles havesize less than 750 microns, preferably less than 500 microns. It may benoted that the fusible polymeric carrier is not a polymer which meltswith substantial degradation or decomposition when heated near themelting point of compound of formula I. The examples of polymers thatdegrade or decompose substantially when subjected to melting or heatingat the temperature near the melting point of compound of formula I,include, but are not limited to, cellulose derivatives, such as forexample, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, acrylate polymers such as poly (methacrylic acidco-ethyl acrylate 1:1), poly (butylmethylacrylate co-dimethylamino ethylmethacrylate co-methyl methacrylate (1:2:1) and similar such polymers.

In yet another specific embodiment, the present invention provides anoral, solid dosage form comprising a mixture consisting essentially ofcompound of formula I

and a fusible polymeric carrier; and

optionally pharmaceutically acceptable excipients, wherein the mixtureis an amorphous dispersion, further wherein the fusible polymericcarrier may be polyvinyl caprolactam-polyvinyl acetate-polyethyleneglycol graft co-polymer. In this embodiment, the amorphous dispersionwhich is a mixture of compound of formula I and fusible polymericcarrier contains only the fusible polymeric carrier and is free of anyother excipient or polymer which was found to degrade or decomposesubstantially when subjected to heating near the melting point of thecompound of formula I. Such polymers or excipients include, but are notlimited to, cellulose derivatives such as for example, hydroxypropylcellulose, hydroxypropyl methyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methyl cellulose phthalate,acrylate polymers such as poly (methacrylic acid co-ethyl acrylate 1:1),poly (butylmethylacrylate co-dimethylamino ethyl methacrylate co-methylmethacrylate (1:2:1) and like.

In preferred embodiment, the weight ratio of the fusible polymericcarrier to compound of formula I is about 7:1. Generally, the amorphousdispersion is in the micronized form. The amorphous dispersion when inthe pulverized form, all the particles have size less than 750 microns,preferably less than 500 microns.

In one another specific embodiment, the present invention provides anoral, solid dosage form comprising a mixture consisting of compound offormula I

and a fusible polymeric carrier; and

optionally pharmaceutically acceptable excipients, wherein the mixtureis an amorphous dispersion, further wherein the fusible polymericcarrier may be polyvinyl caprolactam-polyvinyl acetate-polyethyleneglycol graft co-polymer. Alternatively, the amorphous dispersion is amixture comprising compound of formula I

and a fusible polymeric carrier wherein the mixture is substantiallyfree of excipients which were found to degrade or decomposesubstantially when subjected to heating near the melting point of thecompound of formula I.

The amorphous dispersion of the compound of Formula I and fusiblepolymeric carrier may be directly compressed into tablets or filled intoa capsule, sachet or pouch. More prefereably, the amorphous dispersionis converted into tablets or capsules using pharmaceutically acceptableexcipients. Methods used include, conventional methods such as thosewhere the amorphous dispersion is mixed with the pharmaceuticallyacceptable excipients and converted into tablets by direct compressionor converted into capsules by filling the mixture into capsules oralternatively converted into granules by wet granulation or drygranulation and the granules filled into capsules or compressed intotablets. The oral solid dosage form of the present invention may beobtained by mixing the amorphous dispersion obtained by any one of theabove methods with other conventional excipients like disintegrants,wicking agents, lubricants, surfactants, buffers, diluents andconverting the mixture to all oral solid dosage form, for example it maybe filled into hard gelatin capsule, pouches, sachets, or compressedinto tablets. According to an embodiment, the oral solid dosage form isa hard gelatin capsule filled with the milled amorphous dispersioncomprising compound of formula I and polyvinyl caprolactam-polyvinylacetate-polyethylene glycol copolymer as the fusible polymeric carrier.According to another embodiment, the oral solid dosage form is acompressed tablet comprising the milled amorphous dispersion of compoundof formula I and polyvinyl caprolactam-polyvinyl acetate-polyethyleneglycol copolymer as the fusible polymeric carrier and other conventionalpharmaceutical excipients. In one preferred embodiment, these filledhard gelatin capsules or tablets are packed in closed containers with adesiccant and are stored at 25° C. and 60% relative humidity.

The oral solid dosage form of the present invention is physicallystable. That is the compound of formula I remains in the amorphous stateand does not get converted into crystalline state during its shelf lifewhen stored at ambient conditions. The amorphous nature of compound ofFormula I in the oral solid dosage form may be determined by eitherX-ray diffraction or differential scanning calorimetric analysis (DSC).The XRD spectrum of crystalline form of compound of formula I showscharacteristic diffraction peaks and DSC shows a characteristic meltingpeak at about 246±2° C. The DSC of the oral solid dosage form of thepresent invention does not show melting peak at about 246±2° C.characteristic of crystalline compound of formula I at initial timepoint as well as upon storage at 40° C. and 75% relative humidity for 6months. In order to confirm the amorphous nature, the XRD or DSC of theplacebo excipient blend is also recorded. The absence of characteristic,diffraction peaks in the XRD spectrum, or melting peak at about 246±2°C. in the DSC spectrum, which are characteristic of crystalline compoundof formula I proves that the compound of formula I is in the amorphousstate in the oral solid dosage form of the present invention uponstorage.

The oral solid dosage form of the present invention is also chemicallystable. This means that, each of the degradation impurity such as stageV impurity and N-oxide impurity is less than 0.2% by weight of thecompound of formula I. Also the total impurity, which is sum of knownand unknown impurities, is less than 2% by weight of the compound offormula I. In a preferred embodiments, each of the degradation impuritysuch as stage V impurity and N-oxide impurity is less than 0.2%,preferably in the range of 0.001 to 0.15%, preferably, 0.01 to 0.1% byweight of the compound of formula I. Also, the total impurity is lessthan 2%, preferably, less than 0.001 to 1.5% or 0.01 to 1% by weight ofthe compound of Formula I.

Further, the amorphous dispersion provided an improved oralbioavailability in that the rate and extent of absorption of compound offormula I was significantly enhanced as compared to the plasma levelswhen the crystalline form of compound of formula I in a vehicle wasadministered to dogs. The enhancement in bioavailability was significanti.e. it was found to be in magnitude of about 3, 5, 10, 20, 30, 40, 50times higher as compared to the bioavailability obtained when thecrystalline form of compound of formula I in a vehicle was administeredorally. Thus, the oral, solid dosage of the present invention was notonly stable both chemically and physically, but was also made orallybioavailable.

The pharmaceutically acceptable excipients are the ones that are usedconventionally and are known in the art. These include diluents,disintegrants, wicking agents and surfactants. Examples ofdisintegrating agents used include, but are not limited to, naturalstarch, pregelatinized starch, sodium starch glycolate, microcrystallinecellulose, methylcellulose, croscarmellose, cross-linked cellulose,cross-linked sodium carboxymethylcellulose, cross-linkedcarboxymethylcellulose, cross-linked croscarmellose, cross-linkedstarch, sodium starch glycolate, crospovidone, cross-linkedpolyvinylpyrrolidone, alginic acid, sodium alginate, magnesium aluminumsilicate, agar, guar, locust bean, karaya, pectin, tragacanth, sodiumstarch glycolate, bentonite, cation-exchange resin, sodium laurylsulfate, or in combination thereof. In an embodiment, disintegrant usedin oral solid dosage form is present in an amount ranging from about0.1% to 10% of the total weight of the oral solid dosage form. In anembodiment, surfactant used in oral solid dosage form is present in anamount ranging from about 1% to 10% of the total weight of the oralsolid dosage form. Lubricants or glidants used in the oral solid dosageform are selected from group consisting of, but are not limited to,silicon dioxide, stearic acid, calcium hydroxide, talc, corn starch,sodium stearyl fumarate, alkali-metal and alkaline earth metal salts,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride,leucine, polyethylene glycol, methoxypolyethylene glycol, polyethyleneglycol 4000, polyethylene glycol 5000, polyethylene glycol 6000,propylene glycol, sodium oleate, glyceryl behenate, glycerylpalmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate,and the like. The glidant used in oral solid dosage form is present inan amount ranging from about 0.1% to 3% of the total weight of the oralsolid dosage form. Diluents used in oral solid dosage form are selectedfrom the group consisting of, but are not limited to lactose, starch,mannitol, sorbitol, dextrose, microcrystalline cellulose, dibasiccalcium phosphate, dicalcium phosphate dehydrate, tricalcium phosphate,calcium phosphate, anhydrous lactose, spray-dried lactose,pregelatinized starch, compressible sugar, mannitol,hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetatestearate, sucrose-based diluents, sugar, monobasic calcium sulfatemonohydrate, calcium sulfate dehydrate, calcium lactate trihydrate,dextrates, hydrolyzed cereal solids, amylose, powdered cellulose,calcium carbonate, glycine, kaolin, mannitol, sodium chloride, inositol,bentonite, silicified microcrystalline cellulose and combinationthereof. The diluent used in oral solid dosage form is present in anamount ranging from about 1% to 90% of the total weight of the oralsolid dosage form.

The invention will now be further described by the following examples,which are illustrative rather than limiting.

Examples I and II

TABLE 1 Composition of the amorphous dispersion % by weight IngredientsExample I Example II Compound of Formula I 12 13.3 Polyvinylcaprolactam-polyvinyl 88 43.33 acetate-polyethylene glycol co-polymerPolyethylene glycol — 43.33

The specified amounts of compound of formula I and polyvinylcaprolactum-polyvinyl acetate-polyethylene glycol co-polymer were siftedand mixed in a blender (Example II additionally included polyethyleneglycol 4000). The resulting blend was then charged to a hot meltextruder gradually to a higher temperature (100° C. to 230° C.) yieldingthe melt extrudates. The extrudates were then milled in a comminutingmill fitted with 4.00 mm screen at 2000-2400 RPM which was siftedthrough ASTM #40 and loaded in a blender. The final content wascollected in a suitable container and was subjected to sieve analysis.It was observed that about 100% of the particles were less than 425microns. The milled particles were of the size in the range of about 75microns to 425 microns. Further, about 85% of the particles were of sizeless than 250 microns; about 65% of the particles were of size less than180 microns; about 45% of the particles were of size less than 150microns; and about 15% of the particles were of size less than 75microns. The milled particles of amorphous dispersion had bulk densityin the range of about 0.52 to 0.56 g/ml and had acceptable flowcharacteristics. The extrudates were also subjected to X-Raydiffraction. It was observed that the X-Ray diffraction of meltextrudates of Example I (FIG. 4) did not exhibit any peakscharacteristic of crystalline form of compound of formula I, confirmingits amorphous nature.

Example III

Suitable amount of amorphous dispersion of Example I and the crystallineform of compound of formula I suspended in a vehicle were administeredorally to dogs. Blood samples were withdrawn at various time intervalsand the plasma levels of compound of formula I were recorded. TheC_(max), AUC_(0 to t) and AUC0-_(∞, in in) plasma are tabulated below.

TABLE 2 Bioavailability data Compound of Amorphous Pharmacokineticformula I dispersion of parameters in a vehicle Example I C_(max)(ng/ml) 282 2278 AUC_(0 to t) (ng · hr/ml) 1073 6412 AUC_(0 to ∞) (ng ·hr/ml) 1187 7034

From the above table, it is evident that the oral administration ofamorphous dispersion comprising compound of Formula I, showedsignificantly higher oral bioavailability (C_(max), AUC_(0 to t) &AUC_(0 to ∞)) of compound of formula I as compared to test which did notinclude the compound of formula I as an amorphous dispersion withfusible polymeric carrier, namely polyvinyl caprolactam-polyvinylacetate-polyethylene glycol co-polymer, but was simply dispersed in avehicle. The oral bioavailability was increased to about six times whensame amount of compound of formula I was orally administered.

Example IV

The amorphous dispersion of Example I was mixed with other conventionalexcipients disintegrants, wicking agents, surfactants, lubricants,buffers, diluents and was filled into hard gelatin capsules. The oralsolid dosage form in the form of filled capsules is given below:

TABLE 3 Oral solid dosage form as capsules filled with the amorphousdispersion % by weight of blend Ingredients filled into capsuleAmorphous Dispersion of Example I 78.43 Silicon dioxide 1.57 Sodiumlauryl sulfate 2.55 Crospovidone 9.02 Silicified microcrystallinecellulose 8.43

Procedure: The milled extrudates of amorphous dispersion prepared inexample I, silicon dioxide and sodium lauryl sulfate were sifted andloaded in a blender and mixed. Silicified microcrystalline cellulose andcrospovidone each was sifted separately and were loaded in the blendercontaining the mixture of milled extrudates, silicon dioxide and sodiumlauryl sulfate, and were blended. The blend was filled into hard gelatincapsules of appropriate size to the target fill weight which was filledinto high density polyethylene bottles of appropriate capacity withdesiccant and child resistant closures.

Example V

The capsules of Example IV were subjected to stability conditions at 25°C. and 60% relative humidity for 24 months and the impurities andrelated substances were measured. These capsules were also subjected toaccelerated stability conditions at 40° C. and 75% relative humidity for3 months. The impurities and related substances were measured before(initial) and after storage. The results are provided below in table 4.

TABLE 4 Stability data of oral solid dosage form of Example IV Related40° C./75% 25° C./60% Relative Substances/ Relative humidity humidityfor 24 degradation Initial for three months months impurities % byweight of compound of formula I Stage V Impurity <0.020 <0.020 <0.020N-oxide Impurity <0.039 <0.039 0.082 Highest unknown 0.138 0.157 0.142impurity Total Impurities 0.244 0.293 0.269

The stability study data showed that the degradation impurities likestage V impurity, N-oxide impurity, highest unknown impurity and totalimpurities were well within the acceptable limits. This demonstratedthat the amorphous dispersion of compound of formula I in the oral soliddosage form was chemically stable.

The blend of capsule of Example IV stored at 40° C. and 75% relativehumidity for 6 months in closed container with a desiccant was subjectedto DSC analysis. Also the placebo excipients blend of capsule withoutcompound of formula I was subjected to DSC analysis to rule out theinterference of the excipients or the fusible polymeric carrier (FIG.6). The DSC of crystalline form of compound of formula I is presented inFIG. 5 showing sharp melting peak at about 246±2° C. characteristic ofcrystalline form of compound of formula I. This melting peak was absentin the DSC of blend of capsule of Example IV both before storage (FIG.8) and after it was stored at 40° C. and 75% relative humidity for 6months (FIG. 9). This demonstrated that the compound of formula Iremained in amorphous state on storage throughout its shelf life, i.e.it was physically stable upon storage.

The invention claimed is:
 1. An oral, solid dosage form comprising amixture of compound of Formula I

and a fusible polymeric carrier; and optionally pharmaceuticallyacceptable excipients, wherein the mixture is an amorphous soliddispersion, wherein a weight ratio of the fusible polymeric carrier tothe compound of Formula I is about 7:1, and wherein degradationimpurities are not more than 0.2% by weight of the compound of Formula Iafter the amorphous solid dispersion has been stored at 25° C. and 60%relative humidity for 24 months, wherein the amorphous solid dispersionis in a pulverized form wherein all particles have a size less than 500microns, and wherein the fusible polymeric carrier is not a polymerwhich melts with substantial degradation or decomposition when heatednear the melting point of the compound of Formula I.
 2. The oral, soliddosage form as claimed in claim 1, wherein the fusible polymeric carrieris polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graftco-polymer.
 3. The oral, solid dosage form as claimed in claim 1,wherein the oral, solid dosage form is a capsule filled with theamorphous solid dispersion and pharmaceutically acceptable excipient. 4.The oral, solid dosage form as claimed in claim 1, wherein thedegradation impurities are selected from the group consisting of N-oxideand 4-methyl-3-quinolin-3-ylethynyl-benzoic acid.
 5. The oral, soliddosage form as claimed in claim 1, wherein the amorphous soliddispersion does not comprise a crystalline form of the compound offormula I as determined by a lack of diffraction peaks characteristic ofa crystalline form of the compound of Formula I when measured usingX-ray diffraction, or as determined by a lack of melting peaks of acrystalline form of the compound of Formula I when measured bydifferential scanning calorimetry.
 6. The oral, solid dosage form asclaimed in claim 1, wherein the amorphous solid dispersion is preparedby a method comprising a steps of melting a mixture comprising thecompound of Formula I and the fusible polymeric carrier.
 7. The oral,solid dosage form as claimed in claim 1, wherein the amorphous soliddispersion is prepared by a method comprising a step of melt extruding amixture comprising the compound of Formula I and the fusible polymericcarrier.
 8. The oral, solid dosage form as claimed in claim 1, whereinthe amorphous solid dispersion is free of excipients.
 9. The oral, soliddosage form as claimed in claim 1, wherein the oral, solid dosage formis a hard gelatin capsule filled with the amorphous solid dispersion,wherein the amorphous solid dispersion has been milled.